Tranexamic acid in total hip arthroplasty: An umbrella review on efficacy and safety

Abstract

Purpose

This comprehensive review was conducted to assess the effects of tranexamic acid (TXA) on blood loss, venous thromboembolism (VTE) risk, and wound complications following total hip arthroplasty (THA). Additionally, it sought to evaluate the effects of various TXA dosages, modes of administration, and combinations with other antifibrinolytic drug.

Methods

In search of systematic reviews and meta-analyses on the use of TXA in THA patients, we searched extensively through databases including Scopus, the Cochrane Library, Embase, Medline, the Web of Science, PubMed, and Google Scholar. We discovered 23 meta-analyses covering 32,442 patients overall that fulfilled our study criteria, spanning the period from the creation of these databases until May 2023.

Results

This comprehensive review's meta-analyses, which together examined over 35,000 patients, repeatedly demonstrated how TXA administration during THA successfully lowers perioperative blood loss and the need for transfusions. TXA reduced total blood loss by an average of 151–370 ml, postoperative hemoglobin levels by 0.5–1.1 g/dL, and transfusion rates by 19–26% on average when compared to control groups. The information gathered did not indicate that using TXA significantly increased the risk of VTE or wound complications. When comparing different TXA doses, administration techniques, or its use in conjunction with other anti-fibrinolytic therapies, no discernible differences were found in terms of efficacy or safety outcomes.

Conclusion

The comprehensive review clearly indicates that TXA improves THA outcomes without increasing the risk of adverse events by lowering blood loss and the requirement for transfusions. This insightful information can help surgeons decide whether to use TXA during THA procedures.

1. Introduction

Total hip arthroplasty (THA) is regarded as one of the most efficacious and transformative procedures in the realm of medicine.¹ However, blood loss is a recognized complication of THA, leading to the necessity of blood transfusions. This increases vulnerability to infection, thrombosis, and mortality.² Tranexamic acid (TXA) is an antifibrinolytic agent that induces a reversible inhibition of lysine binding sites on plasminogen molecules. These molecules are paramount in the degradation process of fibrin (Fig. 1).³ The utilization of TXA has been identified as a pivotal treatment strategy for diminishing post-operative blood loss and the requirement for transfusion after THA.⁴ TXA can be administered via various routes, including intravenous (IV), topical, or oral. Additionally, TXA can be utilized in conjunction with other antifibrinolytic agents.⁵

Fig. 1.

The diagram sheds light on the way that TXA functions in the human body. TXA functions as an antifibrinolytic agent by attaching itself to plasminogen and plasmin lysine sites. By effectively blocking fibrin's breakdown, this binding process stops blood clots from forming. This emphasizes how essential TXA is to maintaining the hemostatic balance of the body.

Despite the increasing use of TXA in THA, there exists a substantial discourse about its safety, best dosing, and administration routes. Meta-analyses and systematic reviews have scrutinized the impacts of TXA on blood loss and transfusion risk in THA. These analyses, accompanied by a moderately strong recommendation, demonstrate that TXA diminishes blood loss and transfusion rates without augmenting the vulnerability to venous thromboembolism (VTE) in patients undergoing THA.6, 7, 8 However, further investigation is indispensable to address infrequent occurrences such as pulmonary embolism and perioperative safety concerns.⁸ Moreover, the appropriate TXA dosage, method of administration, and timing of administration remain ambiguous, as do its potential interactions with other antifibrinolytic medications.⁹

To add to and improve the amount of knowledge already available about the use of TXA in THA, it is crucial to routinely review the literature. The objective of this comprehensive analysis was to examine meta-analyses and systematic reviews that evaluate the use of TXA in patients having total hip arthroplasty.

2. Methods

The Preferred Reporting Items for Systematic Reviews and Meta-Analyzes (PRISMA) standards were followed by this umbrella review.¹⁰ Fig. 2 is a flowchart depicting our PRISMA protocol.

Fig. 2.

PRISMA Flow diagram.

2.1. Search strategy

The search approach implemented for this comprehensive review was formulated by a preexisting method proven by Aromataris et al..¹¹ An exhaustive number of 561 individual searches were performed across a variety of databases, including Scopus, the Cochrane Library, Embase, Medline, the Web of Science, PubMed, and Google Scholar from their start until May 2023. Each database was probed using a unique syntax tailored to its specific search guidelines. The following search terms were used: (“Arthroplasties, Replacement, Hip” OR “Arthroplasty, Hip Replacement” OR “Hip Replacement” OR “Arthroplasties” OR “Hip Prosthesis Implantation” OR “Hip Prosthesis Implantations” OR “Implantation, Hip Prosthesis” OR “Prosthesis Implantation, Hip” OR “Replacement Arthroplasties, Hip” OR “Replacement Arthroplasty, Hip” OR “Arthroplasties, Hip Replacement” OR “Hip Replacement Arthroplasty” OR “Hip Replacement, Total” OR “Replacement, Total Hip” OR “Total Hip Replacements” OR “Total Hip Replacement” OR “Total Hip Arthroplasty” OR “Arthroplasty, Total Hip” OR “Hip Arthroplasty, Total” OR “Total Hip Arthroplasties” OR “Hip Prostheses” OR “Prostheses, Hip” OR “Prosthesis, Hip” OR “Femoral Head Prosthesis” OR “Femoral Head Prostheses” OR “Prostheses, Femoral Head” OR “Prosthesis, Femoral Head” OR “Hip Prosthesis”) AND (“AMCHA” OR “trans-4-(Aminomethyl) cyclohexanecarboxylic Acid” OR “t-AMCHA” OR “AMCA” OR “Anvitoff” OR “Cyklokapron” OR” Ugurol” OR “KABI 2161” OR “Spotof “OR “Transamin” OR “Amchafibrin” Or “Exacyl” OR “Tranexamic Acid”) AND (“meta-analysis” OR “systematic review”). The search was further honed by incorporating articles pertinent to systematic reviews and meta-analyses, using relevant Medical Subject Headings (MeSH) terms and keywords. The bibliographies of germane studies were manually inspected to find supplementary studies, showing a thorough approach to the literature search. No limitations were placed on publication status, and only studies published in English were considered.

2.2. Eligibility and study selection

Two authors independently evaluated each title and abstract against our eligibility criteria. Systematic reviews and meta-analyses were selected using pre-defined PICOS criteria (Table 1).¹² When there were discrepancies between authors, a third author was used to reach a majority consensus. This analysis only included studies that offered accurate data about the usage of TXA in comparison to a control group of patients who did not receive TXA. This inclusion criterion is applied to studies comparing TXA with another fibrinolytic agent or comparing different dosages/routes of administration. The details of article choice and exclusion criteria are summarized in the PRISMA flowchart (Fig. 2). Studies were then imported into EndNote® (version 20) and the titles and abstracts into Google Sheets, before removing duplicates.

Table 1.

Eligibility criteria based on the patient, intervention, comparison, and outcomes (PICOS) model.

Element		Criteria
Patients	I	THA patients of all ages and sexes, with all diverse types and sizes of prostheses
	E	Patients with earlier joint replacement surgery, whether it is orthopedic or not, as well as those who have had hemiarthroplasty or multiple arthroplasties
Intervention	I	Any dose or form of TXA administered either before or after surgery
	E	Alternative fibrinolytic to TXA or TXA in combination with other drugs
Comparison	I	Any case-control study
	E	No control
Outcome	I	Total blood loss (including intra and postoperative), postoperative venous thromboembolism and wound complications, transfusion rate, surgical duration, length of stay
	E	Outcomes of neither the volume of blood lost nor the transfusion rate
Design	I	Systematic review or meta-analyses
	E	Methods besides systematic review or meta-analysis and those conducted on animals

I = inclusion criteria, E = exclusion criteria.

2.3. Data Synthesis

Upon the completion of a comprehensive review of the full text and later data extraction, an analytical summary was undertaken to encapsulate the principal characteristics and outcomes of the chosen studies. The collected data included the authors’ names, the year of publication, the number and primary attributes of the study populations, the dosage and method of TXA administration, all pertinent clinical outcomes, and the design of the study (refer to Table 2, Table 3). Given the broad variation in the method, methods, results, and populations of the included reviews, a meta-analysis was believed inappropriate.

Table 2.

Demographics of included studies.

1st Author, Year	Study Type	Studies	Intervention	Patients (n)	Age1	Sex2	TXA (n)/Control (n)	TXA Dosage	Route	Control
Rangasamy, 202142	MA4	4	Primary THA*	450	6.54 to 10.2	40/60	110/340	Loading: 10–50 mg/kg/h, Maintenance: 5–33 mg/kg/h	IV (5)	No TXA (4)/EACA (1)
Sun, 202020	MA	7	Revision THA	4517	NR8	NR	2865/1652	1g bolus preoperatively, 20 mg/kg/h to 1g bolus postoperatively	IV (7)	No TXA (7)
Sukeik, 201931	MA	25	Primary THA	1608	NR	NR	874/734	10–45 mg/kg, IV bolus (12), repeated bolus (6), infusion (4), or mix (3)	IV (25)	P (19)/No TXA (6)
Zhao, 201921	MA	25	Primary THA	2103	44.5 to 73.6	60/40	1010/975	IV: 10–15 mg/kg to 3g, T: 1–3g	IV/NSC (19), T/NSC (3), IV/T/NSC (2), IV/FS/NSC (1)
Liu, 202027	MA	3	Primary THA	1439	59.2 to 65	56/44	593/846	1g (2), 3 g (1)	IV (3)	EACA (3)
Xin, 201919	MA	8	Revision THA	14540	61.4 to 73	60/40	3533/1107	Preoperatively: 10 mg/kg (4), 20 mg/kg (1), Combine: 10 mg/kg before & 1 mg/kg Intra-operative (1) Intraoperatively:1 mg/kg/h infusion (2), Postoperatively: 1 g at once or up to 3h (1)	IV (8)	P (1), No TXA (7)
Zhu, 201828	MA	2	Primary THA	244	64 to 66	58/42	300/346	1 g (1) 10 mg/kg (1)	IV (2)	FS (2)
Yoon, 201822	MA	22	Primary THA	1878	NR	NR	1052/826	IV: 10–15 mg/kg to 3g, T: 1–3 g	IV/P (18), T/P (3), IV/T/P (1)
Franchini, 201816	MA	46	Primary THA	4884	NR	NR	2960/1924	Preoperative in all studies: (10, 15 mg/kg, 1–3 g), Postoperative in 6 studies: (1 mg/kg/h, 1g)	IV (48)	NSC (48)
Kuo, 201818	MA	3	Revision THA	240	NR	NR	149/91	Preoperative: 10 mg/kg or 1g, Postoperative: 1 mg/kg/h, 1g, 10 mg/kg	IV (3)	No TXA (3)
Fillingham, 201843	MA	29	Primary THA	2847	NR	NR	1272/1575	NR	IV (27), T (2)	P (29)
Zhu, 20178	MA	17	Primary THA	951	NR	NR	477/474	IV: 10–15 mg/kg, 200 mg, T: 3 g	IV (16), T (1)	P (12), No TXA (5)
Zhang, 201717	MA	1	Primary THA	108	NR	63/37	54/54	2 h preoperatively, 6 h, and 12 h postoperatively	O (1)	No TXA (1)
Moskal, 201632	MA	16	Primary THA	993	45 to 69	64/36	530/463	Preoperative: 10, 15 mg/kg or 1g, 3g, Postoperative: infusion 1 mg/kg/h or 10 mg/kg bolus	IV (16)	P (16)
Chen, 201644	MA	14	Primary THA	2594	50 to 67.5	NR	946/1648	0.5–3 g	T (14)	P (14)
Xu, 201533	MA	5	Primary THA	645	NR	NR	351/294	2g, 3g during surgery	T (5)	No TXA (2), P (3)
Wei, 201524	MA	14	Primary THA	921	NR	NR	1422/1298	Preoperatively IV: 10 or 15 mg/kg or 1 or 3g, T: 3g (1)	IV (13) T (1)	P (13), NSC (1)
Wang, 201525	MA	8	Primary THA	2330	57.2 to 63	50/50	614/1716	1–5g	T (8)	NSC (8)
Alshryda, 201439	MA	2	Primary THA	228	NR	NR	NR	3g 15 min and 2 h before drain release, and 1g in 20 ml saline	T (2)	P (2)
Zhou, 201330	MA	19	Primary THA	1030	NR	NR	539/491	Preoperatively 10–20 mg/kg or 1g	IV (19)	P (7), NSC (7) No TXA (5)
Gandhi, 201345	MA	14	Primary THA	740	46 to 70.5	54/46	403/337	Preoperatively 10 or 15 mg/kg or 1g	IV (14)	No TXA (3) P (11)
Sukeik, 201036	MA	11	Primary THA	505	NR	NR	NR	Preoperatively 10 or 15 mg/kg or 1g	IV (11)	P (9). NO TXA (2)
Zufferey, 200629	MA	10	Primary THA	562	NR	NR	NR	Preoperatively 10 or 15 mg/kg or 1g	IV (10)	NSC (10)

KEY: TXA = tranexamic acid, NR = not reported, MA = meta-analysis, THA = total hip arthroplasty, O = oral, P = placebo (normal saline), T = topical, FS = fibrin sealant, IV = intravenous, EACA = epsilon-aminocaproic acid, mg = milligram, kg = kilogram, g = gram, h = hour; NSC= Not State Control.

*Among children with cerebral palsy.

1 range of mean ages reported.

2Female (%)/Male (%).

Table 3.

Outcomes of included studies.

1st Author, year	Quality Assessment Tool	Outcomes	Adverse Effects	Results	Authors' Conclusion
Rangasamy, 202142	MINORS, Jadad scale	Surgical blood loss, transfusion requirements, drop in Hb level, LOS, complication rates, Duration of surgery	NR	No significant difference in the duration of surgery, estimated blood loss, drop-in Hb level, or transfusion requirements. Significant reduction in LOS with TXA.	Insufficient evidence to support the routine use of antifibrinolytics in CP children having hip reconstruction.
Sun, 202020	Cochrane Reviewer's Handbook, NOS, Begg's funnel plots	ABT and VTE	NR	Significant reduction in ABT with TXA. No significant difference in VTE between TXA and non-TXA groups.	TXA reduces the risk of ABT in revision THA patients without increasing the risk of VTE events.
Sukeik, 202031	Begg's Funnel plot	TBL, ABT, wound complications, DVT, PE	NR	Significant reduction in wound complications, intraoperative blood loss, postoperative blood loss, TBL, and blood transfusion requirements with TXA. No significant difference in the risk of DVT or PE between groups.	TXA can reduce blood loss, transfusion rates, and wound complications after primary THA surgery.
Zhao, 201921	Cochrane Reviewer's Handbook	Transfusion, TBL, drainage blood loss, DVT	NR	Based on SUCRA: IV TXA and T TXA can significantly reduce the need for transfusion and TBL compared with the control group. IV TXA and T TXA reduced the risk of DVT occurrence compared with the control group.	IV TXA is the most preferable hemostasis method for blood loss control in THA patients without increasing the occurrence of DVT.
Liu, 202027	MINORS, Cochrane risk of bias tool	Transfusion, Hb at discharge, operation time, LOS, DVT, readmission	NR	No significant difference between TXA and EACA groups in blood transfusion rate, transfusion units per patient, Hb level at discharge, operation time, LOS, DVT, or 30-day readmission. EACA was associated with significantly more blood loss than TXA.	EACA led to more blood loss in patients undergoing THA compared with TXA, with no significant differences in other outcomes.
Xin, 201919	Jadad scale, NOS	TBL, Hb reduction, transfusion, RBC units, surgery duration, VTE	NR	No significant difference in TBL, operation duration, and VTE complications between TXA and control groups. Significant reduction in Hb reduction, blood transfusion rate, and number of RBC units transfused with TXA.	IV TXA may reduce Hb reduction, number of RBC units transfused, and blood transfusion rate in patients undergoing revision THA without increasing the risk of VTE and length of operation duration.
Zhu, 201828	GRADE, MINORS, Egger's test	Transfusion, TBL, Hb drop, DVT	Hematoma, infection, fever, DVT	No significant difference between topical FS and IV-TXA in terms of LOS, Hb drop, TBL, and adverse events. Significant reduction in transfusion rate and improvement in Hb values with IV-TXA.	IV-TXA could be more effective in reducing the transfusion rate and improving Hb values without increasing DVT occurrence in comparison with FS.
Yoon, 201822	Cochrane Reviewer's Handbook, adjusted funnel plot	Transfusion, TBL, DVT, PE, drainage	NR	Compared with a placebo, all interventions effectively reduced the need for transfusions and TBL, while a combination of IV and T treatment had a better result than using IV or T TXA alone. No significant difference in the rate of DVT, PE, or total drain output.	Combined TXA treatment can reduce transfusion requirements without the risk of complications (DVT and PE). T administration of TXA alone did not reduce total drainage and had a similar effect to the administration of IV TXA.
Franchini, 201816	Not reported	VTE	NR	Higher incidence of VTE in the intervention group than in the control group during a follow-up of 5 days to 3 months.	The results support the beneficial effect of IV TXA in major orthopedic surgery.
Kuo, 201818	Jadad scale, NOS	TBL, Hb change, RBC units, VTE	NR	The revision THA group had a significantly lower rate of allogeneic blood transfusions, fewer red blood cell transfusions per patient, and a lower mean change in Hb than the control group. No significant difference in blood loss or the risk of VTE events between groups.	IV TXA can significantly reduce blood transfusion requirements following revision TJA, without increasing the risk of VTE.
Fillingham, 201843	AAOS Clinical Practice Guidelines and Systematic Review Methodology	TBL, transfusion	NR	Except for low-dose T TXA, all TXA formulations and doses were statistically superior to placebo in terms of their ability to prevent blood loss and minimize transfusion risk.	Compared to placebo, all methods of TXA administration significantly reduce blood loss and risk of transfusion, with no method of TXA administration proving to be superior to the others.
Zhu, 20178	Jadad scale	TBL, intraoperative/postoperative blood loss, transfusion, Hb drop, LOS, DVT	NR	Significant reduction in TBL, intraoperative blood loss, postoperative blood loss, Hb drop, LOS, and transfusion rate with TXA. No increase in DVT in the TXA group.	TXA IV or T reduced blood loss, transfusion needs, and LOS in THA without increasing VTE risk.
Zhang, 201717	MINORS	Transfusion, Hb drop, drainage volume	NR	The intervention group had significantly higher postoperative Hb, lower Hb drop, lower hidden blood loss, and lower TBL than the control group. No significant difference in drain output and transfused amount between groups. No significant difference in wound complications between the groups.	Oral TXA was associated with less need for transfusion, Hb drop, drain volume, and LOS.
Moskal, 201632	Jadad scale, Cochran's Q-test	TBL, transfusion, DVT, PE, wound complications	DVT, PE, wound hematoma	Significant reduction in ABT, total blood loss, intraoperative blood loss, and postoperative blood loss with TXA. No significant difference in wound complications between the groups. Higher incidence of DVT in the TXA group than in the placebo group.	IV TXA lowers blood loss and ABT rates. Except for DVT, which showed better results with placebo, there was no difference between IV TXA and placebo.
Chen, 201644	GRADE, Oxford Centre for Evidence-based Medicine Levels of Evidence	TBL, transfusion rate, Total drain out	NR	No significant difference in LOS, DVT, and PE between the TXA and placebo groups. Significant reduction in TBL, drainage loss, transfusion rate, and Hb drop with TXA.	T TXA could significantly reduce TBL, drainage loss, and transfusion rates and decrease Hb level following THA, without increasing the risk of VTE.
Xu, 201533	Jadad Scale	Transfusion rate, TBL, DVT	NR	Significant reduction in TBL and transfusion	IV TXA reduced blood loss and transfusion rate without increasing complications in primary THA.
Alshryda, 201439	Cochrane Reviewer's Handbook, British Journal of Orthopedics Surgery Evaluation Tool	TBL and transfusion rate	NR	Significant reduction in transfusion rate (CI: 1.32 to 4.97; p = 0.004) and TBL (−370 ml) with TXA.	T TXA is an effective and safe method of reducing the need for blood transfusion after THA.
Zhou, 201330	Cochrane Reviewer's Handbook	DVT, TBL, intraoperative/postoperative/hidden blood loss, transfusion	DVT, PE, transient dyspnea, nausea, chest pain, low urine output	Significant reduction in TBL, intraoperative blood loss, postoperative blood loss, hidden blood loss, and the need for blood transfusion with IV TXA. No significant difference in DVT, PE, length of hospital stays, and hospital costs between IV TXA and placebo.	IV TXA may reduce blood loss and transfusion needs in patients undergoing THA without increasing the risk of complications.
Gandhi, 201345	Jadad scale	TBL, allogeneic blood transfusion, DVT	NR	Significant reduction in TBL and the number of patients receiving ABT with TXA. No increased incidence of VTE with TXA.	TXA should be considered for routine use in primary THA.
Sukeik, 201036	Cochrane Reviewer's Handbook	TBL, intraoperative/postoperative blood loss, allogeneic blood transfusion, DVT, PE, infection	NR	Significant reduction in TBL, intraoperative blood loss, postoperative blood loss, and the need for ABT with TXA. No significant difference in DVT, PE, infection rate, or other complications between TXA and control groups.	TXA significantly reduced intra-operative blood loss and transfusion requirements after primary THA, with no significant increase in complication rates.
Zufferey, 200629	Begg's funnel plot	TBL, transfusion requirements, VTE rates	NR	Significant reduction in transfusion requirements and TBL with TXA. No increase in VTE rates with TXA.	TXA reduced the risk of ABT significantly in orthopedic surgery.

KEY: NOS = Newcastle-Ottawa Scale, NR = not reported, MINORS = Methodological Index for Nonrandomized Studies, PE = pulmonary embolism, DVT = deep vein thrombosis, VTE = venous thromboembolism, LOS = length of stay, TBL = total blood loss, ABT = allogenic blood transfusion, Hb = hemoglobin, RBC = red blood cell, MD = mean difference, SMD = standardized mean difference, GRADE = Grading of Recommendations Assessment, Development and Evaluation criteria, IV = intravenous, O = oral, T = topical, FS = fibrin sealant, EACA = epsilon-aminocaproic acid, SUCRA = surface under the cumulative ranking curve.

2.4. Quality evaluation

The AMSTAR 2 instrument, which consists of 16 questions that evaluate the critical areas of systematic reviews and meta-analyses, was used to assess the methodological quality of each included review. Responses to each question were classified as “positive,” “negative,” “partial positive,” or “not applicable.” Review quality was divided into four categories based on the total ratings.¹³

3. Results

3.1. Features of included studies

After the elimination of duplicate entries, a total of 369 publications were subjected to title and abstract screening. Consequently, 219 articles were excluded from this study as they did not fulfill the predetermined study criteria (Fig. 2). Subsequently, full-length articles were acquired and assessed, with 23 meta-analyses, published between 2006 and 2021, being included for final analysis (Table 4). These 23 meta-analyses encompassed 76 unique studies, published between 1995 and 2020. A citation matrix depicting the Corrected Covered Area (CCA) for meta-analyses with overlapping studies can be shown in Figures A.1, A.2, A.3.¹⁴. The CCA for the included meta-analyses was 0.11.

Table 4.

Summary of primary outcomes reported as the range of mean difference between tranexamic acid and control cohorts.

Type of outcomes		Number of studies	Population	Range of Mean Difference
Efficacy-outcomes	“Total blood loss”	18	32442	151–370 ml
	“Intraoperative blood loss”	4	N/A	49–104 ml
	“Postoperative blood loss”	5	N/A	176.79–229 ml
	“Hemoglobin change”	8	19111	0.5–1.1 g/dl
Safety-outcomes	“The need for blood transfusion”	18	36037	19–26%
	“Venous thromboembolism”	18	34935	n*
Other-outcomes	“Length of stay”	4	8087	0.84–0.99 day
	“Surgical Duration”	3	4288	1.02 min*
	“Wound complications”	3		1.96%

* Insignificant difference.

Each meta-analysis encompassed multiple outcome variables ranging from 5 to 73 ^{15, 16} (Table 3). The collective number of research participants examined in the 23 meta-analyses varied from 108 to 4884 ^{16, 17}. Three meta-analyses (18 studies) evaluated TXA during revision THA.18, 19, 20

The remaining meta-analyses evaluated TXA use in primary THA. IV was the most often used delivery method throughout the 268 investigations (234 articles)., followed by topical (31 studies),^8,21, 22, 23, 24, 25, 26 and oral (1 study).¹⁷ also, three studies compare the IV and T and Control group.²¹ All 268 unique studies employed No TXA or a placebo for the control group except Liu et al. (3 studies) ²⁷and Rangasan et al. (only one study) which utilized epsilon-aminocaproic acid (EACA) for the control 15 and Zhu et al. (2 studies)which used topical Fibrin Sealant (FS) as the control group.²⁸ 74 studies did Not State the type of Control used for comparison.^{16,21,24,25,29,30}

3.2. Blood loss

Eighteen meta-analyses (32,442 patients) reported total blood loss (TBL) following THA with TXA administration.^4,6,8,17, 18, 19^{,21,22,24,26,}29, 30, 31, 32, 33, 34, 35, 36 Compared to control groups, the average TBL decreased after the administration of TXA, with a range of 151–370 ml. The effect of TXA on intraoperative blood loss was evaluated in four meta-analyses involving 3323 patients. The results showed a mean reduction in intraoperative blood loss ranging from 49 to 104 ml when compared to controls.^8,30,32,36 Similarly, five meta-analyses (5653 patients) included data specifically evaluating postoperative blood loss and found TXA administration to decrease the mean postoperative blood loss between 176.79 and 229 ml when compared to controls.^{4,8,30,32,34,36} Finally, the drop in Hb level was assessed in 8 meta-analyses (19,111 patients), with a mean reduction in Hb drop between 0.5 and 1.1 g/dl compared to controls.^8,15,17, 18, 19^,27,28,34

3.3. Blood transfusions and venous thromboembolism events

Eighteen meta-analyses including 36,037 patients assessed the effect of TXA administration on the requirement for blood transfusions; the results showed a 19–26% drop in the rate of blood transfusions when compared to controls.^8,15,17, 18, 19^,21, 22, 23^,26, 27, 28, 29^,33, 34, 35, 36, 37, 38

The incidence of VTE, as assessed in 17 meta-analyses involving 34,935 patients, did not display statistically significant disparities between the TXA and control cohorts,^16,18, 19, 20, 21, 22^{,24,28,31,33,34} However, One meta-analysis by Moskal and Capps made an exception, reporting a statistically significant (p = 0.0425) increase in the risk of DVT in the Intravenous TXA group (17 out of 418 patients, 4.07%) as compared to the placebo group (6 out of 351 patients, 1.71%).³² In the studies they assessed, there was no significant difference seen between the TXA and placebo groups for other problems that were considered in their meta-analysis. These included pulmonary embolism, clinical wound hematoma, and wound healing issues (i.e., trouble healing and/or superficial infections). This emphasizes the importance that it is to carry out further study in order to completely comprehend the effects of administering TXA in relation to these medical procedures.³²

3.4. Surgical duration and length of stay

The surgical duration of the TXA and control groups was compared in a meta-analysis of three trials including 4,288 patients. The results showed that the TXA groups had a shorter operating time (MD: -1.02 to −6.037 min). But in none of the studies, there were any appreciable differences between the TXA and control groups (p > 0.05).^15,19,27 The length of stay (LOS) was evaluated in four meta-analyses (8,087 patients), wherein it was discovered that the TXA group exhibited a reduced duration of hospitalization (MD: -0.05 to −0.84 days).^8,15,27,34 Only one meta-analysis reported a significant difference among groups, with an MD of 0.35 days [95% CI: -0.12 to 1.80].¹⁵

3.5. Wound complications

Three meta-analyses (3,568 patients) investigated wound complications, two of which yielded insignificant differences between groups, including clinical wound hematoma, infection, and delayed wound healing.^17,32 Zhang et al. only found one case of wound infection in only one study.¹⁷ The Sukeik et al. meta-analysis comprised 1,608 patients. The findings showed that TXA reduced the incidence of wound complications by 2% when compared to the control group, with a risk difference of −0.02 (95% CI: -0.04 to 0.00, p = 0.01).³¹ There were no discernible changes in the incidence of infections between the two groups, with three cases in the control group and none in the TXA group (P-value = 0.90). The infections in the control group consisted of one superficial infection and one deep infection that needed re-operation.³¹

3.6. TXA dosage

The study encompassed meta-analyses that showcased an extensive array of total perioperative TXA doses, varying from 10 to 135 mg/kg. While the topical TXA dosages ranged from 0.5 to 5 g, the majority of the trials used IV TXA doses between 10 and 15 mg/kg or 1–2 g. In one of the meta-analyses, it was shown that topical TXA dosages equal to or exceeding 2g or 15 mg/kg were not more effective in lowering total blood loss than topical doses less than 2g or 15 mg/kg⁸. On the other hand, Zhou et al. found a negative connection between TBL and increasing IV TXA dose in their meta-analysis.³⁰ Fillingham and colleagues saw that every formulation and dosage of TXA, except for the low-dose topical TXA, showed statistically significant superiority over a placebo in the prevention of blood loss. Moreover, all forms and dosages of TXA, except for the oral form, demonstrated statistical superiority over placebo in the reduction of transfusion risk.³⁸ However, most studies either used the same doses or did not compare the effects of different doses in their included studies. See Table 2 for a summary of TXA dosages used.

3.7. Route of administration

Four Meta-analyses found no difference between the route of TXA administration and TBL or transfusion risk, including topical versus IV,^8,24,33 and oral versus IV.¹⁷ According to Yoon et al., the combination of intravenous and topical administration outperformed low-dose, high-dose, low-dose, and high-dose topical TXA in reducing the risk of transfusion.²² while also showing similar efficacy to the oral administration of TXA. Similar findings were reported by Fillingham and colleagues, who found that the combined intravenous and topical administration of TXA reduced the risk of transfusion more than either low- or high-dose intravenous and topical administration and exhibited equivalency to oral TXA.³⁸ Finally, Zhao et al. reported that FS, priced between €450 and €675, is significantly more expensive than TXA, which costs approximately €8 for a therapeutic dose of 10 mg/kg. FS, derived from human plasma products, was found to be more effective and cost-efficient than topical TXA in controlling blood loss.²¹

3.8. Concurrent use of other anti-fibrinolytic agents

The effectiveness and side effects of using other antifibrinolytic medications with TXA, such as FS or EACA aprotinin, have not been examined in a meta-analysis.

3.9. Study quality assessment

Utilizing the AMSTAR-2 tool, it was determined that 9 of the included studies were “high-quality”,^{8,15,17,22,27,28,31,35} 3 studies were “moderate-quality”,^20,33,34 5 studies were “low-quality”,^{23,24,29,32,39} and 7 studies were “critically low quality” ^{4,16,18,19,30,36,38} (Figures A2 and A.3). The primary methodological deficiencies seen in the reviewed studies encompassed overly stringent search methodologies, inadequate characterization of the study population, and insufficient evaluations of potential bias.

4. Discussion

The care of possible problems, such as perioperative blood loss, becomes increasingly important as the number of THA surgeries performed annually grows. The occurrence of bleeding, along with the consequent necessity for transfusion after THA, enhances the likelihood of infection, thrombosis, and mortality 2. Thus, it is paramount to prove efficacious protocols to reduce perioperative bleeding during THA. The use of TXA, while becoming more widespread, is not without ambiguity surrounding its safety and efficacy. Because of this, there has become a mounting body of literature evaluating the effects of TXA on THA. The purpose of this comprehensive study was to evaluate the safety and efficacy of TXA in THA as documented by previous meta-analyses and determine if the literature has any support for the optimal dose and administration procedures (Fig. 3 illustrates the main advantage of TXA in the THA).

Fig. 3.

The primary advantages of utilizing TXA in THA procedures.

This thorough review's findings demonstrate that TXA usage in THA significantly lowers a number of blood loss markers, including TBL, blood loss during and after surgery, hemoglobin level decline, and blood transfusion frequency. Nevertheless, one meta-analysis found a heightened likelihood of DVT associated with the administration of TXA.³². This is inconsistent with most of the other studies, which showed no increase in DVTs with TXA use.^16,18, 19, 20, 21, 22^{,24,28,31,33,34} The meta-analysis had a smaller sample size and a distinct method in comparison to the other investigations, which conceivably influenced the findings. Additionally, the incidences of DVT were mild and infrequent and did not affect the overall outcomes of the patients. Therefore, TXA may still be considered a secure and effective preventative measure for hemorrhage during the perioperative period of THA, but further investigation is needed to confirm this and find the variables that shape the propensity of DVT when administering TXA.

The effect of TXA on LOS following THA resulted in inconclusive findings in four meta-analyses.^8,15,27,34 Rangasamy et al. did report a significantly shorter LOS, however, this meta-analysis included children with cerebral palsy and is difficult to generalize to the typical THA population.¹⁵ This emphasizes the need for more RCTs to be conducted to assess the impact of TXA on LOS when THA is present.

The safety and efficacy of the TXA when taken with the THA were shown to be minimally affected by modifications in the dose and mode of administration. Nevertheless, it is important to note that the observed results could potentially be attributed to the diversity and restricted quantity of research incorporated in each subgroup analysis. Hence, there is a need for more RCTs of superior quality to find the most effective treatment regimen for TXA in THA.

No clear superiority of any method of the TXA administration (IV, Topical, Oral, or combined) was found, although some studies suggested that combined or IV TXA might have some advantages over other routes of administration. The dose of TXA depended on the route of administration. The studies used a variety of protocols, with TXA doses ranging from 10 to 20 mg/kg (up to a maximum of 1 g). 10–20 mg/kg were often followed by IV and oral administration for a period of 3–12 h. On the other hand, the range for topical and intra-articular treatment was 3 g–250 mg in 5–100 ml of saline. In terms of total blood loss, hemoglobin decrease, transfusion rates, and risk of thromboembolic consequences, the meta-analyses that were reviewed did not uncover any statistically significant differences between the IV, topical, oral, or combination methods of TXA administration. It is crucial to remember that more thorough studies with bigger sample numbers are still required to determine which method of administering TXA is best for patients having primary total hip arthroplasty.

Our comparative review of many studies shows that TXA given during THA reliably lowers the amount of blood lost overall (from 151 to 370 ml), the amount of blood needed for transfusions (from 19 to 26%), and the length of hospital stay (from 0.05 to 0.84 days) when compared to control groups. Complicated data, however, differed. Although one research revealed a higher DVT rate with IV TXA, the majority of studies found no discernible change in VTE rates. The outcomes of wound infection and problems with healing were yet unclear. Zhang et al.'s study shown that TXA is more effective than EACA at reducing blood loss and the need for transfusions in THA patients. These results support our conclusion that TXA's safety and efficacy in THA are not considerably affected by its dose or mode of administration.⁴⁰ Contrarily, Poeran et al. discovered that TXA treatment decreased the chance that THA patients would need blood transfusions and shortened their hospital stays, but they also noticed a higher risk of VTE connected with TXA use.⁴¹. Our study found no significant effect of TXA on the duration of hospitalization, and TXA usage did not significantly alter the occurrence of VTE.

Our findings support previous research by emphasizing the usefulness of TXA in lowering blood loss and the need for transfusions. There are differences in certain outcomes nevertheless, such the duration of stay, the incidence of seizures, and VTE. The study's publishing and selection bias is a main weakness. Only English-language publications were included in the analysis, which may have led to the exclusion of relevant research. The quality and methodology of the studies we included in our analysis, however, varied widely, which raised the possibility of confounding variables and jeopardized the general dependability of the findings. Moreover, the study did not assess cost effectiveness, patient-reported outcome measures, or functional restoration—all of which are significant outcomes. Future research must thus look into these results in addition to providing more thorough and supported information about the usage of TXA in THA.

5. Conclusions

This thorough systematic review offers strong data that highlights the effectiveness of TXA in reducing blood loss and transfusion requirements in patients undergoing THA. The meta-analyses included in this review consistently show that, when compared to control groups, the use of TXA significantly lowers total blood loss (which can range from 151 to 370 ml), postoperative hemoglobin drop (which can range from 0.5 to 1.1 g/dL), and blood transfusion rates (which can drop by 19–26%). The combined evidence provides strong support for TXA's efficacy in reducing perioperative bleeding and the consequences that follow in THA.

Regarding safety, the majority of the reviewed trials did not discover a statistically significant distinction in the frequencies of wound infections, VTE, or problems with healing between the TXA and control groups. While a single meta-analysis did note a higher incidence of DVT in patients receiving intravenous TXA, the majority of the data does not suggest a higher risk of these side effects from TXA usage. However, it is important to emphasize that more high-quality randomized controlled studies are still required to determine the optimal procedures for TXA administration and to completely define the safety profile. This humanistic viewpoint places a strong emphasis on the value of patient safety and wellbeing in the search for efficient medical interventions.

Funding statement

None, This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Data availability

All data analyzed and synthesized in this study are sourced from previously published systematic reviews and meta-analyses. The references for these studies are provided in the reference section of the article, and readers can access the original publications for detailed data.

Guardian/patient's consent

Not applicable.

Ethical statement

Not applicable.

CRediT authorship contribution statement

Mohammad Ghorbani: Conceptualization, and design of the study, acquisition of data, Formal analysis, Writing – original draft, of the manuscript, and final approval of the manuscript. Seyed Hassan Sadrian: Acquisition of data, Formal analysis, and final approval of the manuscript. Rezvan Ghaderpanah: Formal analysis, and final approval of the manuscript. Colin C. Neitzke: Writing – original draft, of the manuscript, and final approval of the manuscript. Brian P. Chalmers: Writing – original draft, of the manuscript, and final approval of the manuscript. Saeid Esmaeilian: Acquisition of data, and final approval of the manuscript. Elham Rahmanipour: Final approval of the manuscript. Ali Parsa: Writing – original draft, of the manuscript, and final approval of the manuscript.

Declarations of competing interest

None.

APPENDICES.

Fig. A.1.

Citation Matrix with Corrected Covered Area (CCA). $CCA=\frac{N-r}{rc-1}=0.11$. N = number of included publications in all reviews (including double counting), r = number of publications excluding duplicates, and c = number of reviews we included.

Fig. A.2.

Individual study quality assessment by AMSTAR-2 risks of bias tool. The specific question correlating to Q1-Q16 is further depicted in Figure A.3.

Fig. A.3.

Aggregate study quality assessment by AMSTAR-2 risks of bias tool.